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I want to go back a second to the
end of last time because in the
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closing moments there, we, or
at least I, got a little bit
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lost, and where
the plusses and
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minuses were at
a certain table.
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And, I want to go back and make
sure we've got that straight.
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We were talking about a situation
where we were trying to use genetics,
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and the phenotypes that might
be observed in mutants to try to
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understand the biochemical pathway
because we're beginning to try to
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unite the geneticist's point of
view who looks only at mutants,
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and the biochemist's point of view
who looks at pathways and proteins.
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And, I had hypothesized that there
was some biochemists who had thought
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up a possible pathway for the
synthesis of arginine that involved
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some precursor,
alpha, beta, gamma,
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where alpha is turned into beta;
beta is turned into gamma; and gamma
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is used to turn into
arginine. And, hypothetically,
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there would be some enzymes:
enzyme A that converts alpha,
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enzyme B that converts beta,
and enzyme C that converts gamma.
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And, we were just thinking about,
what would the phenotypes look like
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of different arginine auxotrophs
that had blocks at different stages
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in the pathway. If I had
an arginine auxotroph that
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had a block here because let's say
a mutation in a gene affecting this
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enzyme, or at a block here
at a mutation affecting, say,
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the gene that encodes enzyme C,
how would I be able to tell very
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simply that they were in
different genes? Last time,
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we found that we could tell they
were in different genes by doing a
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cross between a mutant
that had the first mutation,
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and a mutant that had the second
mutation, and looking at the double
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heterozygote, right? And,
if in the double heterozygote
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you had a wild type or a normal
phenotype, then they had to be in
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different genes,
OK? Remember that?
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That was called a test
of complementation.
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That was how we were able to sort
out which mutations were in the same
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gene, and which mutations
were in different genes.
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Now we can go a step further.
When we've established that they're
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in different genes, we
can try to begin to think,
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how do these genes relate
to a biochemical pathway?
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I wanted to begin to introduce,
because it'll be relevant for today,
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this notion: so, suppose I had a
mutation that affected enzyme A so
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that this enzymatic step
couldn't be carried out.
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Such a mutant, when I
just try to grow it on
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minimal medium won't be able to grow.
If I give it the substrate alpha,
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it doesn't do it any good because
it hasn't got the enzyme to convert
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alpha. So, given alpha, it
won't grow. But if I give it
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beta, what will happen? It
can grow because I've bypassed
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the defect. What about if
I give it gamma? Arginine?
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Now, if instead the mutation were
affecting enzymatic step here,
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then if I give it
on minimal or medium
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but it can grow on gamma.
What about this last line?
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If I have a mutation and
the last enzymatic step,
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minimal medium can't grow with
alpha, can't grow with beta,
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can't even grow with gamma.
But, it can grow with arginine
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because I've bypassed that step.
So, I get a different phenotype,
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the inability to
grow even on gamma,
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but I can grow on arginine. Now,
here, if I put together those
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mutants and make a double mutant,
a double homozygote, let's say,
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that's defective in both A and B,
which will it look like? Will it be
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able to grow on minimal medium?
Will it be able to grow on alpha?
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Will it be able
to grow on beta?
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Will it be able to grow on gamma
and arginine? What about if I have a
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double mutant in B and C,
minus, minus, minus, minus,
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plus? So this looks the same as
that. This looks the same as that.
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And so, by looking at
different mutant combinations,
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I can see that the phenotype of B
here is what occurs in the double
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mutant. So, this phenotype is
epistatic to this phenotype.
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Epistatic means stands upon,
OK? So, phenotypes, just like
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phenotypes can be recessive or
dominant, you can also speak about
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them being epistatic. And
epistatic means when you have
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both of two mutations
together at the epistatic
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then one of them is epistatic
to the other, perhaps.
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It will, in fact, be
the one that is present.
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So, this is not so easy to do
in many cases because if I take
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different kinds of mutation
affecting wing development,
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and I put them together in the same
fly, I may just get a very messed up
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wing, and it's very hard to
tell that the double mutant has a
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phenotype that looks like
either of the two single mutants.
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But sometimes, if they fall very
nicely in a pathway where this
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affects the first step,
this affects the second step
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this affects the third step,
this affects the fourth step,
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then the double mutant
will look like one of those,
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OK? And, that way you can somehow
order things in a biochemical
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pathway. Now, notice,
this is all indirect,
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right? This is what geneticists did
in the middle of the 20th century to
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try to figure out how to connect
up mutants to biochemistry.
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Actually, that's not true.
It's what geneticists still do
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today because you might think
that Well, we don't need to do this
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anymore, but in fact geneticists
constantly are looking at mutants
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and making connections trying to
say, what does this double combination
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look like? What does that
double combination look like,
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and how does that tell us
about the developmental pathway,
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which cell signals which cell?
This turns out to be one of the
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most powerful ways to figure out
what mutations do by saying the
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combination of two mutations
looks like the same as one of them,
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allowing you to order the
mutations in a pathway.
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And, there's no general way to
grind up a cell and order things in a
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pathway. Genetics is a very
powerful tool for doing that.
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Now, there are some ways to
grind up cells and order things,
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but you need both of these
techniques to believe stuff.
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Anyway, I wanted to go over that,
because it is an important concept,
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the concept of epistasis, the
concept of relating mutations to
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steps and pathways, but what
I mostly want to do today
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is go on now to talk about genetics
not in organisms like yeast or fruit
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flies or even peas,
but genetics in humans.
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So, what's different about genetics
in humans than genetics in yeast?
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You can't choose who mates
with whom. Well, you can.
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I mean, in the days of arranged
marriages maybe you couldn't,
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but you can choose who mates
with whom, but only for yourself,
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right? What you can't do is
arrange other crosses in the human
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population as an experimentalist.
Now, your own choice of mating,
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unfortunately or fortunately perhaps
produces too few progeny to be
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statistically significant. As
a parent of three, I think about
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what it would take to raise a
statistically significant number of
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offspring to draw any conclusions,
and I don't think I could do that.
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So, you're absolutely right. We
can't arrange the matings that
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we want in the human population.
So, that's the big difference.
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So, can we do genetics anyway?
How do we do genetics even though
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we can't arrange the matings
the way we'd like to? Sorry?
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Well, family trees. We have to
take the matings as we find them in
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the human population. You
can talk to somebody who might
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have an interesting phenotype,
I don't know, attached earlobes,
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or very early heart disease,
or some unusual color of eyes,
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and begin to collect a
family history on that person.
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It's a little bit of a dodgy thing
because you might just be relying on
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that person's recollection. So,
if you were really industrious
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about this, you'd go check out each
of their family members and test for
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yourself whether they have the
phenotype. People who do serious
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human genetic studies often go and
do that. They have to go confirm,
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either by getting hospital records
or interviewing the other members of
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the family, etc. So, this
is not as easy as plating
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out lots of yeasts
on a Petri plate.
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And then you get pedigrees. And
the pedigrees look like this.
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Here's a pedigree. Tell
me what you make of it.
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Now, symbols: squares are males,
circles are females by convention,
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a colored in symbol means
the phenotype that we're
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interested in studying at the
moment. So, in any given problem,
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somebody will tell you, well,
we're studying some interesting
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phenotype. You often have
an index case or a proband,
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meaning the person who
comes to clinical attention,
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and then you chase back in the
pedigree and try to reconstruct.
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So, suppose I saw a
pedigree like this.
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What conclusions could I draw?
Sorry? Recessive, sex link trait;
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why sex link trait? So,
let's see if we can get your
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model up here. You think
that this represents
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sex-linked inheritance. So,
what would the genotype be of
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this male here? Mutant:
I'll use M to denote a
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mutant carried on the X chromosome,
and a Y on the opposite chromosome.
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What's the genotype
of the female here?
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So, it's plus over plus where I'll
use plus to denote the gene carried
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on the normal X chromosome.
OK, and then what do you think
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happened over here?
So, mutant over plus,
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you mate to this male who is plus
over plus. Why is that male plus
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over plus? Oh,
right, good point.
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It's not plus over plus. It's
plus over Y. Why is that male
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plus over Y as opposed
to mutant over Y?
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He'd have the mutant phenotype.
So, he doesn't have the mutant
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phenotype so he can infer he's plus
over Y. OK, and then what happens
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here? Mutant over Y; this is plus
over Y. How did this person get
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plus over Y? They just the
plus for mom, and the daughters,
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Y from dad, and a plus from mom.
That's cool. Now, what about the
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daughters there?
They're plus over plus,
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or M over plus? Is one,
one, and one the other? Well,
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in textbooks it's always plus
over plus and M over plus,
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but in real life? We don't know,
right? So, this could be plus over
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plus, or M over plus,
we don't know, OK? Now,
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what about on this side
of the pedigree here?
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What's the genotype
here? Plus over Y, OK.
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Why not mutant over Y?
Because if they got the mutant,
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it would have to come from the, OK,
so here, plus over plus, and then
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here, everybody is normal because
there's no mutant allele segregated.
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Yes? Yeah, couldn't there
just be recessive? I mean,
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it's a nice story
about the sex link
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but couldn't it be recessive?
So, walk me through it being
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recessive. M over plus,
plus over plus. Wait, wait,
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wait, hang on. Could this be M over
plus, and that person be affected?
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It's got to be M over M,
right so mutants over mutants
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but that's possible. Yeah,
OK. So, what would this
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person be? Plus over plus,
let's say, come over here. Now,
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what would this person be? M plus.
It has to be M plus because, OK,
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and what about this person
here? M plus, now what about the
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offspring? So, one
of them is M over M,
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plus over plus, and two M pluses.
Does it always work out like that?
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[LAUGHTER] No, it doesn't
always work out like that at all.
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So, I'm just going to write
plus over plus here just to say,
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tough, right? In real life, it
doesn't always come out like that.
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What about over here? It would
have to be plus over plus.
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Why not? It doesn't because it
could be M over plus and have no
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effect at offspring by chance,
right? But, you were going to say
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it's plus over plus because in the
textbooks it's always plus over plus
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in pictures like this, right?
And then, it all turns out
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to be pluses and mutants, and
pluses and mutants, and all that,
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right? Well, which
picture's right?
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Sorry? You don't know. So,
that's not good. There's supposed
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to be answers to these things.
Could either be true? Which is
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more likely? The one on the left?
Why? More statistically probable,
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how come? Because it is. It
may not quite suffice as a fully
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complete scientific
answer though.
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Yes? Yep. Well, but I have
somebody who is affected
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here. So, given that I've gotten
affected person in the family --
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yeah, so it is actually, you're
right, statistically somewhat
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less likely that you would have two
independent M's entering the same
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pedigree particularly
if M is relatively rare.
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If M is quite common, however,
suppose M were something
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was a 20% frequency in the
population, then it actually might
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be quite reasonable that this could
happen. So, what would you really
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00:17:28 --> 00:17:33
want to do to test this? Sorry?
Well, if you found any females here
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maybe you'd be able to conclude that
it was autosomal recessive because
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females never show a
sex-linked trait. Is that true?
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00:17:46 --> 00:17:53
No, that's not true. Why not?
You're right. So, you just have to
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be homozygous for it on
the X. So, having a single
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00:18:00 --> 00:18:09
female won't, I mean, she's
not going to take that as
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evidence. Get an affected female
and demonstrate that all of her male
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00:18:18 --> 00:18:28
offspring show the trait.
Cross her with, wait, wait.
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00:18:28 --> 00:18:31
This is a human pedigree guys
[LAUGHTER]. Whew! There are issues
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involved here, right? You
could introduce her to a
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00:18:35 --> 00:18:39
normal guy, [LAUGHTER] but whether
you can cross her to a normal guy is
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00:18:39 --> 00:18:43
not actually allowed. So,
you see, these are exactly the
216
00:18:43 --> 00:18:46
issues in making sense
out of pedigrees like this.
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00:18:46 --> 00:18:50
So, what you have to do is you
have to collect a lot of data,
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00:18:50 --> 00:18:54
and the kinds of characteristics
that you look for in a pedigree,
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00:18:54 --> 00:18:58
but they are statistical
characteristics, and
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notwithstanding -- So, this
could be colorblindness or
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00:19:02 --> 00:19:06
something, but notwithstanding
the pictures in the textbook of
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00:19:06 --> 00:19:10
colorblindness and all that, you
really do have to take a look at
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00:19:10 --> 00:19:14
a number of properties.
What are some properties?
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One you've already referred to
which is there's a predominance in
225
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males if it's X-linked. Why
is there a predominance in
226
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males? Well, there's a
predominance in males because if I
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00:19:27 --> 00:19:32
have an X over Y and I've
got a mutation paired on
228
00:19:32 --> 00:19:36
this X chromosome, males
only have to get it on one.
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Females have to get it on both, and
therefore it's statistically more
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00:19:40 --> 00:19:44
likely that males will get it.
So, for example, the frequency of
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00:19:44 --> 00:19:48
colorblindness amongst males
is what? Yeah, it's 8-10%,
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00:19:48 --> 00:19:52
something like that. I
think it's about 8% or so.
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00:19:52 --> 00:19:56
And, amongst females,
well, if it's 8% to get one,
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00:19:56 --> 00:20:00
what's the chance
you're going to get two?
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00:20:00 --> 00:20:08
It's 8% times 8% is a
little less than 1% right?
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00:20:08 --> 00:20:17
It's 0.64%, OK, in females.
So, we'll just go 8%
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00:20:17 --> 00:20:25
squared. So in males, 8% in
females, less than one percent.
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00:20:25 --> 00:20:33
So, there is a
predominance in males
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00:20:33 --> 00:20:39
of these sex-linked traits. Other
things: affected males do not
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00:20:39 --> 00:20:46
transmit the trait to the kids,
in particular do not transmit it to
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00:20:46 --> 00:20:53
their sons, right, because
they are always sending the
242
00:20:53 --> 00:21:00
Y chromosomes to their
songs. Carrier females
243
00:21:00 --> 00:21:10
transmit to half of their sons,
and affected females transmit to all
244
00:21:10 --> 00:21:20
of their sons. And, the
trait appears to skip
245
00:21:20 --> 00:21:30
generations, although I
don't like this terminology.
246
00:21:30 --> 00:21:35
It skips generations. These
are the kinds of properties
247
00:21:35 --> 00:21:40
that you have.
So, hemophilia,
248
00:21:40 --> 00:21:45
a good example of this, if I
have a child with hemophilia,
249
00:21:45 --> 00:21:50
male with hemophilia, would you
be surprised if his uncle had
250
00:21:50 --> 00:21:55
hemophilia? Which uncle would
it be, maternal or paternal?
251
00:21:55 --> 00:22:00
The maternal uncle would
have hemophilia most likely.
252
00:22:00 --> 00:22:04
It's always possible it could be
paternal. This is the problem with
253
00:22:04 --> 00:22:08
human genetics is you've got to
get enough families so the pattern
254
00:22:08 --> 00:22:12
becomes overwhelmingly clear,
OK, because otherwise, as you can
255
00:22:12 --> 00:22:16
see with small numbers, it's
tough to be absolutely certain.
256
00:22:16 --> 00:22:20
So, these are properties
of X linked traits.
257
00:22:20 --> 00:22:24
How about baldness? Is
baldness, that's a sex-linked
258
00:22:24 --> 00:22:28
trait? How come? You don't
see a lot of bald females.
259
00:22:28 --> 00:22:32
Does that prove it's sex linked?
Sorry? Guys are stressed more.
260
00:22:32 --> 00:22:37
[LAUGHTER] Is there evidence that
it has anything to do with stress?
261
00:22:37 --> 00:22:41
Actually, it has to do with
excess testosterone it turns out,
262
00:22:41 --> 00:22:46
that high levels of testosterone
are correlated with male pattern
263
00:22:46 --> 00:22:51
baldness, but does the fact that
males become bald indicate that this
264
00:22:51 --> 00:22:56
is a sex linked trait? No.
Just because it's predominant
265
00:22:56 --> 00:23:01
in male, we have to check
these other properties.
266
00:23:01 --> 00:23:05
Is it the case that bald
fathers tend to have bald sons?
267
00:23:05 --> 00:23:09
Any evidence on this point?
Common-sensical evidence from
268
00:23:09 --> 00:23:14
observation? It's pretty clear.
It's very clearly not a sex-linked
269
00:23:14 --> 00:23:18
trait. It's a sex-limited trait,
because in order to show this you
270
00:23:18 --> 00:23:23
need to be male because the high
levels of testosterone are not found
271
00:23:23 --> 00:23:27
in females even if they have the
genotype that might predispose them
272
00:23:27 --> 00:23:33
to become bald if they were male.
So, it actually is not a sex-linked
273
00:23:33 --> 00:23:40
trait at all, and it's very clear
that male pattern baldness does run
274
00:23:40 --> 00:23:48
in families more vertically. So,
you've got to be careful about
275
00:23:48 --> 00:23:55
the difference between
sex linked and sex limited,
276
00:23:55 --> 00:24:02
and sex linked you can really pick
out from transmission and families.
277
00:24:02 --> 00:24:10
OK, here's another
one. New pedigree.
278
00:24:10 --> 00:24:43
She married twice here.
OK, what do we got?
279
00:24:43 --> 00:24:53
Yep? She married again. She
married twice. She didn't have
280
00:24:53 --> 00:25:01
any offspring the second
time. But that happens,
281
00:25:01 --> 00:25:06
and you have to be able
to draw it in the pedigree.
282
00:25:06 --> 00:25:12
She's entitled, all right.
OK, so she got married again,
283
00:25:12 --> 00:25:17
no offspring from this marriage.
That's her legal symbol. You guys
284
00:25:17 --> 00:25:22
think that's funny.
It's real, you know?
285
00:25:22 --> 00:25:28
OK, that doesn't mean she's married
to two people at the same time.
286
00:25:28 --> 00:25:33
This is not a temporal picture.
So, what do we got here? Yep?
287
00:25:33 --> 00:25:38
Sorry, of this person? Well,
I'm drawing them as an empty
288
00:25:38 --> 00:25:44
symbol here, indicating that we
do not think they have the trait.
289
00:25:44 --> 00:25:50
They're not carriers. How do
you propose to find that out?
290
00:25:50 --> 00:25:56
Look at the children. Well,
the children are affected. They
291
00:25:56 --> 00:26:02
could be carriers. The
data are what they are.
292
00:26:02 --> 00:26:09
You've got to interpret it.
Does this person have to be a
293
00:26:09 --> 00:26:16
carrier? What kind of
trait do you think this is?
294
00:26:16 --> 00:26:23
Dominant? Does this look like
autosomal dominant to you?
295
00:26:23 --> 00:26:30
Yep? Oh, not all the
kids have the trait
296
00:26:30 --> 00:26:34
in the first generation,
and if this was dominant,
297
00:26:34 --> 00:26:38
they'd all have it? What's a
possible genotype for this person?
298
00:26:38 --> 00:26:42
Mutant over plus. And, these
kids could be mutant over plus.
299
00:26:42 --> 00:26:46
This could be plus over plus,
and this could be plus over plus,
300
00:26:46 --> 00:26:50
mutant over plus, plus
over plus, mutant over plus,
301
00:26:50 --> 00:26:54
and plus over plus would be
one possibility. On average,
302
00:26:54 --> 00:26:58
what fraction of the kids
should get the trait? About half
303
00:26:58 --> 00:27:06
the kids, right? So, let's
see what characteristics
304
00:27:06 --> 00:27:18
we have here. We see the
trait in every generation.
305
00:27:18 --> 00:27:30
On average, half the
kids get the trait.
306
00:27:30 --> 00:27:42
Half of the offspring of an
affected individual are affected.
307
00:27:42 --> 00:27:54
What else? Males and females?
Roughly equal in males and females?
308
00:27:54 --> 00:28:02
Sorry? One,
two, three,
309
00:28:02 --> 00:28:08
four, five to two.
So, it's a 5:2 ratio?
310
00:28:08 --> 00:28:13
Oh, in the offspring it's a 2:1
ratio. So, this is like Mendel.
311
00:28:13 --> 00:28:19
You see this number and you say,
OK, 2:1. Isn't that trying to tell
312
00:28:19 --> 00:28:24
me something? Not with six
offspring. That's the problem is
313
00:28:24 --> 00:28:30
with six offspring, 2:1 might
be trying to tell you 1:1.
314
00:28:30 --> 00:28:34
And it is. If I had a dominantly
inherited trait where there's a
315
00:28:34 --> 00:28:39
50/50 chance of each offspring
getting the disease and it was
316
00:28:39 --> 00:28:44
autosomal, not sex linked,
there would be very good odds of
317
00:28:44 --> 00:28:48
getting two males and one female
because it happens: flip coins and
318
00:28:48 --> 00:28:53
it happens. So, you have
to take that into account,
319
00:28:53 --> 00:28:58
and here you see what else we have.
Roughly equal numbers of males and
320
00:28:58 --> 00:29:03
females, they transmit equally,
and unaffecteds never transmit.
321
00:29:03 --> 00:29:07
This would be the classic
autosomal dominant trait.
322
00:29:07 --> 00:29:11
Right, here this mutant
would go mutant over plus,
323
00:29:11 --> 00:29:15
mutant over plus, plus over plus,
mutant over plus, plus over plus,
324
00:29:15 --> 00:29:19
plus over plus, and you'd
see here that three out of
325
00:29:19 --> 00:29:23
the five here, and one,
two, three out of the six
326
00:29:23 --> 00:29:27
there: that's a little more
than half but it's small numbers
327
00:29:27 --> 00:29:33
here, right? This is a
classic autosomal dominant
328
00:29:33 --> 00:29:39
as in the textbooks. Yes?
Turns out not to make too
329
00:29:39 --> 00:29:46
much of a difference. It
turns out that there's lots of
330
00:29:46 --> 00:29:53
genome that's on either. And
so, it is true that males are
331
00:29:53 --> 00:30:00
more susceptible to
certain genetic diseases.
332
00:30:00 --> 00:30:04
So, it'll be some excess,
but it won't matter for this.
333
00:30:04 --> 00:30:09
Now, in real life it doesn't
always work so beautifully.
334
00:30:09 --> 00:30:13
We'll take an example: colon cancer.
There are particular autosomal
335
00:30:13 --> 00:30:18
dominant mutations here that
cause a high risk of colon cancer.
336
00:30:18 --> 00:30:23
People who have mutations
in a certain gene, MLH-1,
337
00:30:23 --> 00:30:27
have about a 70% risk of getting
colon cancer in their life.
338
00:30:27 --> 00:30:33
But notice, it's not 100%. You
might have incomplete penetrance.
339
00:30:33 --> 00:30:41
Incompletely penetrance means not
everybody who gets the genotype gets
340
00:30:41 --> 00:30:48
the phenotype. Not all
people with the M over plus
341
00:30:48 --> 00:30:56
genotype show the phenotype.
Once you do that, it messes up our
342
00:30:56 --> 00:31:03
picture colossally,
because, tell me,
343
00:31:03 --> 00:31:09
how do we know that this person over
here is not actually M over plus.
344
00:31:09 --> 00:31:15
Maybe they're cryptic. They
haven't shown the phenotype.
345
00:31:15 --> 00:31:21
And maybe, it'll appear in the
next generation. That'll screw up
346
00:31:21 --> 00:31:27
everything. It screws up our rule
about not transmitting through
347
00:31:27 --> 00:31:32
unaffected, it screws up the
rule about not being shown in
348
00:31:32 --> 00:31:36
every generation, and it
will even screw up our 50/50
349
00:31:36 --> 00:31:41
ratio because if half the
offspring get M over plus,
350
00:31:41 --> 00:31:46
but only 70% of that half show
the phenotype, then only 35% of the
351
00:31:46 --> 00:31:50
offspring will show the phenotype.
Unfortunately, this is real life.
352
00:31:50 --> 00:31:55
When human geneticists really
look at traits, many mutations,
353
00:31:55 --> 00:32:00
most except the most severe
are incompletely penetrant.
354
00:32:00 --> 00:32:04
And so you have to really begin to
gather a lot of data to demonstrate
355
00:32:04 --> 00:32:08
that you're dealing with an
autosomal dominant trait that's
356
00:32:08 --> 00:32:12
incompletely penetrant. And
then there are other issues.
357
00:32:12 --> 00:32:16
There's a gene on chromosome
number 17 called BRCA-1,
358
00:32:16 --> 00:32:20
mutations in which predisposed to a
very high risk of breast cancer but
359
00:32:20 --> 00:32:24
only in women. Males carry
the mutation and do not
360
00:32:24 --> 00:32:28
have breast cancer. There
are other mutations that do
361
00:32:28 --> 00:32:32
cause breast cancer in males.
Males have breast tissue,
362
00:32:32 --> 00:32:36
and can have breast cancer, but
the one on chromosome 17 does
363
00:32:36 --> 00:32:40
not. And so, there you would only
see this transmitted through females.
364
00:32:40 --> 00:32:45
It would skip into males
without showing a phenotype,
365
00:32:45 --> 00:32:49
etc. So, in real life,
life's a bit more complicated.
366
00:32:49 --> 00:32:53
All right, so autosomal dominance.
Now, let's take one more pedigree.
367
00:32:53 --> 00:32:58
Sorry? Sex limited,
but not sex linked.
368
00:32:58 --> 00:33:03
So, on chromosome 17, which
is a bona fide autosome,
369
00:33:03 --> 00:33:08
but it's sex limited in that
phenotype can only show itself in an
370
00:33:08 --> 00:33:13
individual who happens to be female.
Yes? Sorry? How come autosomal
371
00:33:13 --> 00:33:19
recessive? So, if that
left guy up there is
372
00:33:19 --> 00:33:24
actually a heterozygote,
and up there that individual,
373
00:33:24 --> 00:33:30
so if we had a homozygote,
homozygote, heterozygote,
374
00:33:30 --> 00:33:33
homozygote, ooh, you can
interpret that pedigree if
375
00:33:33 --> 00:33:37
you want to as an autosomal
recessive, provided that M is pretty
376
00:33:37 --> 00:33:40
frequent in the population.
That's right. Human geneticists,
377
00:33:40 --> 00:33:44
in fact, to really prove that
they've got the right model,
378
00:33:44 --> 00:33:48
collect a lot of pedigrees
and run a computer model.
379
00:33:48 --> 00:33:51
The computer model first
tries out autosomal recessive,
380
00:33:51 --> 00:33:55
tries out autosomal dominant,
tries out dominant with incomplete
381
00:33:55 --> 00:33:59
penetrance, and for every possible
model figures out the statistical
382
00:33:59 --> 00:34:03
probability that you would
see such data under that model.
383
00:34:03 --> 00:34:05
And when the data become
overwhelming and you say,
384
00:34:05 --> 00:34:08
yeah, with one pedigree, any
pedigree I draw on the board,
385
00:34:08 --> 00:34:11
it could actually fit almost any for
the models. It doesn't say this in
386
00:34:11 --> 00:34:14
the textbooks, but
it's true. I get enough
387
00:34:14 --> 00:34:17
pedigrees, and eventually I say the
odds are 105 times more likely that
388
00:34:17 --> 00:34:20
this collection of pedigrees would
arise from autosomal dominance,
389
00:34:20 --> 00:34:22
inheritance with incomplete
penetrance of about 80%.
390
00:34:22 --> 00:34:25
Then, from autosomal recessive
inheritance, then I get to write a
391
00:34:25 --> 00:34:28
paper about it. That's
really what human
392
00:34:28 --> 00:34:32
geneticists do is they
have to collect enough,
393
00:34:32 --> 00:34:36
now, any other organism,
you'd just set up a cross,
394
00:34:36 --> 00:34:41
but you can't. And, as long
as we have nontrivial models,
395
00:34:41 --> 00:34:46
we really have to collect a lot of
data. Let's take the next pedigree,
396
00:34:46 --> 00:34:50
great, that you're thinking
like a human geneticist.
397
00:34:50 --> 00:34:55
It's very good. Here's the
next pedigree. Actually,
398
00:34:55 --> 00:35:00
I'm going to reverse
it. There we go.
399
00:35:00 --> 00:35:03
What's that? Who knows? You
can't tell. Good, I've got you
400
00:35:03 --> 00:35:07
up to training to the point where,
but in textbooks, this would be
401
00:35:07 --> 00:35:11
autosomal recessive.
Or it could be anything.
402
00:35:11 --> 00:35:15
You know that, right? But the
textbooks would show you this
403
00:35:15 --> 00:35:18
picture as an autosomal recessive.
But of course, what else could it
404
00:35:18 --> 00:35:22
be? It could be an autosomal
dominant with incomplete penetrance.
405
00:35:22 --> 00:35:26
It could be sex linked. It
could be a lot of things.
406
00:35:26 --> 00:35:30
It could also be, I haven't
told you the phenotype.
407
00:35:30 --> 00:35:34
What if the phenotype here
was getting hit by a truck?
408
00:35:34 --> 00:35:38
[LAUGHTER] Would you
tend to observe this? Yep,
409
00:35:38 --> 00:35:42
so getting hit by a truck, for
example, if someone gets hit by
410
00:35:42 --> 00:35:46
a truck, it's unlikely either
their parents were hit by a truck,
411
00:35:46 --> 00:35:50
or going back several generations
that their grandparents were hit by
412
00:35:50 --> 00:35:54
a truck. So, how do you tell
being hit by a truck from,
413
00:35:54 --> 00:35:58
I mean, that is to say, how
do you know that something's
414
00:35:58 --> 00:36:01
genetic at all? When it's
relatively rare and it
415
00:36:01 --> 00:36:04
pops up in a pedigree, how
do you know it's genetic?
416
00:36:04 --> 00:36:07
Because of the DNA. But, I mean,
it takes a lot of work to find the
417
00:36:07 --> 00:36:10
gene and all that as we'll come to
the course. You might want a little
418
00:36:10 --> 00:36:13
bit of assurance before you go write
the grant to the NIH and say I'm
419
00:36:13 --> 00:36:16
going to find the gene for this
because you write it and say I'm
420
00:36:16 --> 00:36:19
going to find the gene
for getting hit by a truck,
421
00:36:19 --> 00:36:22
and they're going to write back and
say show me that it's worth spending
422
00:36:22 --> 00:36:25
money to find that gene.
Show me that it's true. So,
423
00:36:25 --> 00:36:28
what kind of things would we look
for? If we wanted to show something
424
00:36:28 --> 00:36:32
was autosomal recessive in a
population, what would we do?
425
00:36:32 --> 00:36:40
More data. So, we
collect a lot of families,
426
00:36:40 --> 00:36:48
and what would we see? As we
collected more and more families,
427
00:36:48 --> 00:36:56
we begin to see what things?
Sometimes we might see families like
428
00:36:56 --> 00:37:04
this, or we might see
families like this. [LAUGHTER]
429
00:37:04 --> 00:37:08
If both parents were mutants,
all the children would be mutant,
430
00:37:08 --> 00:37:13
right? We'd color them in mutant.
Is that true? Well, first off, it
431
00:37:13 --> 00:37:18
depends. Some of the things we
want to study are extremely severe
432
00:37:18 --> 00:37:23
medical genetical phenotypes,
and they're not going to live to
433
00:37:23 --> 00:37:28
have children. So, that's
an issue that you have
434
00:37:28 --> 00:37:33
to deal with. But, it
is true that if it was
435
00:37:33 --> 00:37:37
autosomal recessive, a mating
between two homozygotes for
436
00:37:37 --> 00:37:42
that gene would transmit.
[LAUGHTER] What if they were all in
437
00:37:42 --> 00:37:46
the same car? Which is
a very important part,
438
00:37:46 --> 00:37:51
because we joke about the car,
but diet, things like that, are
439
00:37:51 --> 00:37:55
familial correlated environmental
factors. There are environmental
440
00:37:55 --> 00:38:00
factors that correlate
within a family.
441
00:38:00 --> 00:38:04
And so, it's not trivial
to make this point. So,
442
00:38:04 --> 00:38:09
all right, we'll be able to
demonstrate what's the real proof of
443
00:38:09 --> 00:38:14
Mendelian inheritance here?
Because they could all be in the
444
00:38:14 --> 00:38:19
same car, or they all eat the same
kind of food or something like that,
445
00:38:19 --> 00:38:24
which predisposes them a certain way.
So, we're going to want some better
446
00:38:24 --> 00:38:29
proofs of these things.
How about Mendelian ratios?
447
00:38:29 --> 00:38:34
Mendelian ratios anyone? No,
because it could be incomplete
448
00:38:34 --> 00:38:38
autosomal dominance. I
don't want to mess you up.
449
00:38:38 --> 00:38:42
On the exams, you guys can think
cleanly about simple things.
450
00:38:42 --> 00:38:46
But, this could be dominant
with incomplete penetrance,
451
00:38:46 --> 00:38:50
though the TA's are going to hate
me because I'm telling you that,
452
00:38:50 --> 00:38:54
anyway, what about Mendelian ratios?
How about something that's a pretty
453
00:38:54 --> 00:38:58
good prediction? What
fraction of the offspring will
454
00:38:58 --> 00:39:02
be affected? We get
a lot of families,
455
00:39:02 --> 00:39:07
line them all up. What
fraction of the offspring?
456
00:39:07 --> 00:39:12
A quarter. Now, that's a
hard and fast prediction.
457
00:39:12 --> 00:39:17
One quarter of the offspring are
effective. When I have a mating
458
00:39:17 --> 00:39:22
between two homozygotes,
so what am I going to do?
459
00:39:22 --> 00:39:28
I'm going to go out. I'm going
to collect a lot of families.
460
00:39:28 --> 00:39:31
Maybe I'll collect 100 families
because it'll be a particular
461
00:39:31 --> 00:39:35
disease, diastrophic dysplasia
or something like that,
462
00:39:35 --> 00:39:39
xeroderma pygmentosa,
ataxia teleangiectasia,
463
00:39:39 --> 00:39:43
and I will go to the disease
foundation, and I will get all the
464
00:39:43 --> 00:39:46
pedigrees for all the families,
and I'll see how many times it was
465
00:39:46 --> 00:39:50
one affected, two affected, three
affected, etc. And on average,
466
00:39:50 --> 00:39:54
the proportion affecteds will be
a quarter, except it's not true.
467
00:39:54 --> 00:39:58
If I actually do that, I find that
the ratio of affecteds is typically
468
00:39:58 --> 00:40:03
more like a third.
It isn't a quarter.
469
00:40:03 --> 00:40:09
Now, this should disturb you
greatly because you know full well
470
00:40:09 --> 00:40:16
that M over plus by M over plus
should give you a quarter affecteds.
471
00:40:16 --> 00:40:23
But when you actually look
at human families, it's not.
472
00:40:23 --> 00:40:30
Why? In other words, when
we count up all the matings
473
00:40:30 --> 00:40:33
between heterozygotes, we'll
collect all the matings that
474
00:40:33 --> 00:40:37
produce one affected child.
We'll collect all the matings that
475
00:40:37 --> 00:40:41
produce two affected children.
We'll collect all the matings that
476
00:40:41 --> 00:40:45
produce three affected children.
But, we will fail to collect those
477
00:40:45 --> 00:40:48
matings between homozygotes that
produce zero affected children.
478
00:40:48 --> 00:40:52
And so, we will systematically
overestimate the proportion.
479
00:40:52 --> 00:40:56
Of course, what we really have to
do is go out and get all of those
480
00:40:56 --> 00:41:00
couples who were both carriers,
but because they had a small number
481
00:41:00 --> 00:41:04
of children didn't happen
to have an affected child.
482
00:41:04 --> 00:41:08
That's not very easy to do
especially when you don't know the
483
00:41:08 --> 00:41:12
gene in advance. So, when
human geneticists try to
484
00:41:12 --> 00:41:16
go out and measure the
one-quarter Mendelian ratio,
485
00:41:16 --> 00:41:21
you can't. But what you
can do is the following,
486
00:41:21 --> 00:41:25
conditional on the first trial
being affected, now what will be the
487
00:41:25 --> 00:41:30
proportion of subsequent
children who are affected?
488
00:41:30 --> 00:41:33
A quarter. If I make it conditional,
conditioning on having a first child
489
00:41:33 --> 00:41:37
who's affected, number
one child who's affected,
490
00:41:37 --> 00:41:40
then I know I've got a
mating between heterozygotes.
491
00:41:40 --> 00:41:44
Subsequent offspring now
do not have that bias.
492
00:41:44 --> 00:41:47
And so, as a matter of fact, you
think this pretty cool thought,
493
00:41:47 --> 00:41:51
right? You've got a condition on
one. It turns out there's a very
494
00:41:51 --> 00:41:54
famous paper about cystic fibrosis
where somebody forgot this point and
495
00:41:54 --> 00:41:58
made a huge big deal in the
literature about the fact that a
496
00:41:58 --> 00:42:02
third of the kids on average
had cystic fibrosis in these
497
00:42:02 --> 00:42:06
families, and proposed all sorts
of models about how cystic fibrosis
498
00:42:06 --> 00:42:11
might be advantageous and would lead
to fertility increases and all that.
499
00:42:11 --> 00:42:16
In fact, it was just a failure to
correct for this little statistical
500
00:42:16 --> 00:42:20
bias. OK, this is what human
geneticists do is they've got to
501
00:42:20 --> 00:42:25
deal with the popular, now,
there's one other trick that
502
00:42:25 --> 00:42:30
you can use to know that
something is autosomal recessive.
503
00:42:30 --> 00:42:37
That trick is this.
To site this trick,
504
00:42:37 --> 00:42:45
I have to go back to a person
called Archibald Garrett.
505
00:42:45 --> 00:42:53
Archibald Garrett was a
physician in London around 1900.
506
00:42:53 --> 00:43:01
Garrett studied children
with the trait alkoptonuria.
507
00:43:01 --> 00:43:06
Alkoptonuria was what alkopton
means black. Uria means urine.
508
00:43:06 --> 00:43:11
They had black urine. This was
evident because their urine turned
509
00:43:11 --> 00:43:16
black on treatment with alkaline.
How would you treat urine with
510
00:43:16 --> 00:43:22
alkaline. How would people know
this? Sorry? Outhouses with lime,
511
00:43:22 --> 00:43:27
yeah, and who's going to look at
the children's urine, or something
512
00:43:27 --> 00:43:32
like that? But you're
on the right track.
513
00:43:32 --> 00:43:38
How about diapers? You
wash diapers, cloth diapers,
514
00:43:38 --> 00:43:43
in alkaline. They turn black. This
was evident from black diapers.
515
00:43:43 --> 00:43:49
The kids' urine would turn black.
So, he observed this, and you know
516
00:43:49 --> 00:43:54
what Garrett noticed is when he
studied, children alkoptonuria,
517
00:43:54 --> 00:44:00
he found that a very
large fraction of affected
518
00:44:00 --> 00:44:10
offspring were in fact produced
from matings of first cousins.
519
00:44:10 --> 00:44:20
Consanguineous matings: now you
laugh, but in fact consanguinity has
520
00:44:20 --> 00:44:30
been something that has been
favored in many societies,
521
00:44:30 --> 00:44:35
and in Britain, particularly
amongst the upper class
522
00:44:35 --> 00:44:40
in Britain in 1900, marriage
or first cousins was quite
523
00:44:40 --> 00:44:45
common, but not as common as he
observed. He found that eight out
524
00:44:45 --> 00:44:50
of 17 alkoptonuria patients were the
products of first cousin marriages.
525
00:44:50 --> 00:44:55
That's way off the charts
because it's nearly a half,
526
00:44:55 --> 00:45:00
when in fact the typical rate in
Britain might have been about 5%.
527
00:45:00 --> 00:45:03
So, on the basis of that in the
early 1900's, Garrett was able to
528
00:45:03 --> 00:45:07
show only a few years after the
rediscovery of Mendel's work that
529
00:45:07 --> 00:45:11
this property of recessive traits,
enrichment in the offspring of
530
00:45:11 --> 00:45:15
consanguineous marriages,
was a clear demonstration of
531
00:45:15 --> 00:45:18
Mendelian inheritance.
Not only did he do that,
532
00:45:18 --> 00:45:22
but Garrett knew because of
the work of some biochemists,
533
00:45:22 --> 00:45:26
and this is way cool, that
the problem with the urine was
534
00:45:26 --> 00:45:30
that these patients put out in
their urine a lot of what's called
535
00:45:30 --> 00:45:42
homogentisic acid, HGA,
which basically is a phenolic
536
00:45:42 --> 00:45:54
ring. What Garrett did was he,
and that stuff turns black on
537
00:45:54 --> 00:46:02
exposure to air. What might
produce from the things
538
00:46:02 --> 00:46:07
you've learned already
some kind of ring like that?
539
00:46:07 --> 00:46:12
What building blocks do you know
have rings like that of things
540
00:46:12 --> 00:46:17
you've studied already?
Phenylalanine, tyrosine both have
541
00:46:17 --> 00:46:22
rings. Suppose somebody had
problems breaking down homogentisic
542
00:46:22 --> 00:46:27
acid. Suppose there was some
pathway where proteins were
543
00:46:27 --> 00:46:32
broken down into amino
acids including phenylalanine
544
00:46:32 --> 00:46:37
and tyrosine. And, they
were broken down into
545
00:46:37 --> 00:46:42
homogentisic acid. And
they were broken down into I
546
00:46:42 --> 00:46:47
don't know what. And,
suppose like we had up there,
547
00:46:47 --> 00:46:52
patients had a mutation in that
enzyme. What would happen if I fed
548
00:46:52 --> 00:46:57
patients a lot of protein? In
their urine, you would recover
549
00:46:57 --> 00:47:01
lots of homogentisic acid. Suppose
I fed them a lot of tyrosine.
550
00:47:01 --> 00:47:05
I'd get a lot of homogentisic acid
because the body couldn't break it
551
00:47:05 --> 00:47:09
down. Suppose I fed them
a lot of phenylalanine.
552
00:47:09 --> 00:47:13
They would excrete a
lot of homogentisic acid.
553
00:47:13 --> 00:47:16
Suppose I fed them homogentisic
acid. I would get quantitative
554
00:47:16 --> 00:47:20
amounts of homogentisic acid.
Garrett did this. These are the
555
00:47:20 --> 00:47:24
days before institutional
review boards, you know,
556
00:47:24 --> 00:47:28
informed consent. It turns out it's
harmless feeding them proteins and
557
00:47:28 --> 00:47:33
things like that.
But in fact, Garrett,
558
00:47:33 --> 00:47:39
in 1911, worked out that this trait
had to be recessive because of its
559
00:47:39 --> 00:47:46
population genetics, and
inferred a biochemical pathway
560
00:47:46 --> 00:47:53
by feeding different things along
the way and was able to connect a
561
00:47:53 --> 00:48:00
mutation in a gene to a problem
with a specific biochemical pathway.
562
00:48:00 --> 00:48:05
Sorry, 1908: this was his
Croonian Lecture in 1908.
563
00:48:05 --> 00:48:10
Eight years after the rediscovery
of Mendel, he's able to connect
564
00:48:10 --> 00:48:15
genetic defect, showing
it's genetic by transmission,
565
00:48:15 --> 00:48:20
to biochemical defect showing that
he has a pathway that he can feed
566
00:48:20 --> 00:48:25
things into. And, it all
blocks up at the inability to
567
00:48:25 --> 00:48:30
metabolize homogentisic acid. He
has connected gene to enzyme by
568
00:48:30 --> 00:48:35
1908. What do you
think the reaction to
569
00:48:35 --> 00:48:39
this was? Polite bewilderment,
and it sunk like a stone. Nobody
570
00:48:39 --> 00:48:43
was prepared to hear this. This
is very much like Mendel in my
571
00:48:43 --> 00:48:47
opinion. Now, he was a
distinguished professor.
572
00:48:47 --> 00:48:52
It was the Croonian Lecture. He
got lots of accolades and all that,
573
00:48:52 --> 00:48:56
and people said, what a
lovely lecture that was,
574
00:48:56 --> 00:49:00
and proceeded to completely forget
this connection between genes and
575
00:49:00 --> 00:49:05
enzymes, genes and proteins. It
was not until 40 years later or
576
00:49:05 --> 00:49:09
so that Beadle and Tatum,
working with a fungus, actually
577
00:49:09 --> 00:49:13
rosper not yeast, demonstrated
that all these mutants
578
00:49:13 --> 00:49:17
interfered with the ability to
digest or to make particular amino
579
00:49:17 --> 00:49:21
acids, and wrote this up as the one
gene, one enzyme hypothesis of how
580
00:49:21 --> 00:49:25
genes encode enzymes, and
won the Nobel Prize for this
581
00:49:25 --> 00:49:30
work, but in fact in
their Nobel address,
582
00:49:30 --> 00:49:34
Beetle and Tatum noted, actually,
you know, Garrett kind of
583
00:49:34 --> 00:49:39
knew all this. But,
people weren't ready,
584
00:49:39 --> 00:49:43
yet, to digest it. Genetics
had just come along,
585
00:49:43 --> 00:49:48
Biochemistry had just really been
invented in the last ten years,
586
00:49:48 --> 00:49:52
and the idea of uniting genetics
and biochemistry was just something
587
00:49:52 --> 49:57
people weren't prepared
for yet. More next time.